P454: ACUTE MYELOID LEUKEMIA (AML) WITH IDH1 AND IDH2 MUTATIONS CAN BE EFFECTIVELY RISK STRATIFIED BASED ON THE PRESENCE ADVERSE RISK GENOMIC FEATURES.
Authors: Aniket Bhide, Gaurav Chatterjee, Sweta Rajpal, Swapnali Joshi, Vishram Terse, Dhanlaxmi Shetty, Anant Gokarn, Sachin Punatar, Nishant Jindal, Bhausaheb Bagal, Lingaraj Nayak, Hasmukh Jain, Navin Khattry, Manju Sengar, Prashant Tembhare, Sumeet Gujral, Papagudi Subramanian, Nikhil Patkar
Journal: HemaSphere (2023)

Background: Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) mutations are frequently mutated in AML accounting for nearly 15-20% of patients. IDH1 mutations are limited to the R132 locus whereas IDH2 mutations involve R140 and R172 hotspots. There is conflicting and inconsistent published data regarding morphologic remission rate (CR), overall survival (OS), relapse free survival (RFS) and measurable residual disease (MRD) positivity with respect to genomic features that may influence outcomes of IDH1/2 mutated AML. Aims: To evaluate the clinical, laboratory and genomics features, responses to chemotherapy, and outcomes of different subtypes of IDH mutated AML. Methods: A total of 98 adult patients (median: 44 years) of IDH1/2 mutated AML were accrued over a 4-year period from January 2018 to July 2022. Patients were diagnosed as per the 2017 WHO classification and risk stratified using FISH and conventional karyotyping as per standard recommendations. Targeted sequencing was performed using a 52 gene myeloid panel and subsequently using a 227 gene leukemia panel. Sequencing data was analysed using open source bioinformatics. The presence of mutations in ASXL1, BCOR, EZH2, SF3B1, SRSF2, STAG2, U2AF1 and ZRSR2 genes as well as specific cytogenetic abnormalities were used to define AML with myelodysplasia related changes (AML-MR). Together AML-MR associated genetic abnormalities as well as presence of RUNX1 or TP53 gene mutations were classified as adverse genomic risk. MRD was measured using 10 or 16 colour multicolour flow cytometry at end of induction (PI MFC-MRD). Most patients (73, 74.5%) were treated with conventional “3 + 7” therapy and the rest were treated with azacytidine +/- venetoclax. The median follow-up was 14.9 months. Results: The IDH1 (IDH1 R132C/H/S/G) mutation was most commonly observed (51%) followed by IDH2 R140 (Q/W; 30.6%) and IDH2 R172K (18.4%). Patients with IDH2 R172 mutations presented with a lower total leucocyte count at presentation (R172 vs R132, R172 vs R140; p=<0.0001, p=0.01). NPM1 mutations were mutually exclusive to IDH2 R172K group. Adverse genomic risk was seen in 21(21.4%) patients. None of these harboured NPM1 mutations and this group was enriched in IDH2 R172K mutation (57.1% versus 7.8% in IDH mutated AML without adverse genomic risk features, p<0.0001). Majority of IDH2 R172K mutated AML failed to achieve morphological remission (86.7%) and 100% of these patients were PI MFC-MRD positive. Majority of patients with adverse genomic features were PI MFC-MRD positive (88.2% v/s 30%, p<0.0001) compared to others. Presence of NPM1 mutation did not predict for a favorable OS in IDH1/2 mutated AML (p = 0.18). There was no difference (p=0.6) in the median OS for IDH2 R172 mutated AML(25.8 months, 95% CI:16.7 to 35.0) as compared to IDH2 R140 (27.6 months, 95% CI:22.8 to 33.0) and IDH1 R132 (31.7 months, 95% CI: 23.4 to 34.4) mutated AML. Mutations in genes implicated in clonal hematopoesis (DNMT3A, TET2, ASXL1) did not predict for a different outcome (p=0.6). Presence of adverse genomic features predicted for a significantly lower median OS [21.3 months (95%CI: 12.9 to 23.6)] when compared to IDH1/2 mutated AML patients that lacked these abnormalities [32.1 months (95%CI: 25.8 to 33.3), p<0.0001] as seen in Figure 1. Summary/Conclusion: We demonstrate that the ELN2022 risk stratification is highly predictive of outcome in AML with IDH1/2 mutations. Our data seems to indicate that IDH2 R172K mutated AML is enriched with adverse cytogenetics and mutations in ASXL1, BCOR, EZH2, SF3B1, SRSF2, STAG2, U2AF1, ZRSR2, TP53 and RUNX1 genes.Keywords: Genomics, AML